CN1705664A - Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine - Google Patents

Abstract

A process for preparing (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine. The process includes the steps of contacting a compound containing a mixture of R- and S-isomers and having the formula with an effective amount of a chiral organic acid in the presence of an organic solvent and an effective amount of an organic carboxylic acid for converting the R-isomer into an acid salt of the S isomer, wherein the organic solvent is capable of solubilizing the compound containing the mixture of R- and S-isomers, while precipitating the acid salt and the organic carboxylic acid is different from the chiral organic acid; neutralizing the acid salt with a base to provide an S-isomer of a chiral ketone of the formula reacting the chiral ketone with an organic amine in the presence of a Lewis acid to provide the corresponding imine and reducing the imine.

Description

(S, S)-cis-2-benzhydryl-3-benzylamino-quinuclidine preparation method

field of invention

The present invention relates to a process for the preparation of the title compound, (S,S)-cis-2-benzhydryl-3-benzylaminoquinucidine (4), which is useful in the preparation of optically active quinuclidine analogues is a useful intermediate, and the optically active quinucidine analog has utility as a non-peptide antagonist of substance P.

Background of the invention

Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which produce a rapid stimulatory effect on smooth muscle tissue. Substance P is a pharmaceutically active neuropeptide that is produced in mammals and has a characteristic amino acid sequence as described in US Patent No. 4,680,283. Various antagonists of substance P can be prepared from the title compound; for example, U.S. Patent No. 5,162,339 discloses antagonists of substance P of formula 2, wherein ^R is methoxy and ^R is independently selected from isopropyl, tert-butyl radical, methyl, ethyl and sec-butyl.

Reductive amination of cis-2 ^- benzhydryl-3 can be achieved by using a suitable aldehyde ^of formula R CHO, wherein R is defined as a benzaldehyde derivative in which the benzene ring is substituted with R ^{and R} as described above -Amino-quinucidine 1, preparation of antagonists of these substances P:

Various reagents, such as hydrogen , this reductive amination is achieved in the presence of a suitable metal catalyst, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc and hydrochloric acid, dimethylborane sulfide or formic acid. An alternative is to convert 1 to 2 by alkylation with a suitable electrophile as taught eg in US Patent Nos. 5807867 and 5939433 and WO92/21677. A further alternative for the conversion of 1 to 2 is the acylation of 1 with an activated carboxylic acid derivative followed by reduction of the resulting amide with a reagent such as lithium aluminum hydride, as described in WO92/21677 and the Journal of Medicinal Chemistry, 35 , 2591 (1992).

cis-2-benzhydryl-3-amino-quinuclidine 1, which is an intermediate in the formation of 2, is obtained from 3-benzylamine-2-benzhydrylquinuclidine 4 by using It can be obtained by debenzylation with hydrogen and catalyst. The preparation of benzylamine 4 is described by Warawa in the Journal of Medicinal Chemistry, 18, 587 (1975) and is shown in Scheme 1. The method starts with 3-quinuclidinone 5 (obtained by the method of Clemo et al. in the Journal of the Chemical Society (London) p. 1241 (1939)), which is condensed with benzaldehyde to give enone 6 . Enone 6 reacts with phenylmagnesium chloride to form 2-benzhydryl-3-quinuclidinone 3. Reduction of the alkylated ketone 3 with benzylamine affords 4.

Process 1

This method is adapted to allow access to aryl and quinuclidine analogs, as described in WO92/20676 and US Patent No. 5,162,339. Methoxybenzylamine has been used in place of benzylamine because it facilitates hydrolytic removal to afford amine 1 as well as hydrogenolysis as described in US Patent Nos. 5,807,867 and 5,939,433.

The use of 9-BBN, formed from the reaction of benzylamine with ketone 3, for imine reduction has been advocated as this maximizes the formation of the desired cis isomer of 4. This method is described in the Journal of Medicinal Chemistry, 35, 2591 (1992).

In all of these instances, the material was racemic. Separation of enantiomers on compounds 1, 2 or 4 has been performed by classical resolution techniques. This is illustrated, for example, by the method described in U.S. Patent No. 5,138,060, in which the salt is purified by crystallization of racemate 7 from ethyl acetate with (-)-mandelic acid, followed by recrystallization from ethyl acetate, and The methoxyphenyl derivative 7 is isolated by treatment with base to release the free amine product to provide the desired (-)-isomer. In the described procedure, by using (1R)-(-)-10-camphorsulfonic acid, N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl ]-2-(Benzhydryl)-1-azabicyclo[2.2.2]oct-3-amine, as described in WO97/03984.

In Japanese Patent No. 07025874, Murakami et al. disclosed the use of D-tartaric acid for the resolution of cis-3-amino-2-benzhydrylquinucidine (1) in methanol. The diastereoisomers were also separated using an intermediate carbamate to obtain 1 as a single enantiomer, as described in Journal of Medicinal Chemistry, 35, 2591 (1992).

Summary of the invention

The invention relates to a preparation method of (S, S)-cis-2-benzhydryl-3-benzylaminoquinuclidine. The method of the present invention comprises, in the presence of an organic solvent and an effective amount of an organic carboxylic acid, making a compound containing a mixture of R- and S-isomers and having the following formula:

Contacting with an effective amount of a chiral organic acid converts the R-isomer to the acid salt of the S-isomer. According to the method of the present invention, the organic solvent used is capable of solubilizing compounds containing a mixture of R- and S-isomers while precipitating acid salts. Furthermore, the organic carboxylic acids used in the process of the invention are different from the chiral organic acids used.

The contacting steps described above are performed so that dynamic kinetic resolution occurs. That is, the contacting step of the present invention is performed using reactants and conditions that drive the reaction to form the S isomer. According to the present invention, this dynamic kinetic resolution is obtained when an effective amount of an organic carboxylic acid is used to solubilize quinuclidone and provide an acidic environment to racemize the R isomer to the S isomer. Preferably, the organic carboxylic acid has no chirality. Preferably at least 1 equivalent of organic carboxylic acid is used relative to quinuclidone, and more preferably greater than 1 equivalent. Also, dynamic kinetic resolution can be obtained when using an effective amount of chiral organic acid of at least 1 equivalent, preferably greater than 1 equivalent.

After the contacting step, the resulting acid salt is neutralized with an organic base to provide the S-isomer of the chiral ketone of the formula:

Next, the chiral ketone is reacted with an organic amine in the presence of a Lewis acid to provide the corresponding imine, which is then reduced. According to the present invention, an effective amount, preferably at least 1 equivalent, and more preferably greater than 1 equivalent of Lewis acid is used for optimal conversion. Scheme 2 below describes the method of the present invention.

In a preferred embodiment, the starting material is racemic 2-benzhydryl-3-quinuclidinone (3). In a preferred embodiment, the process starts from racemic 2-benzhydryl-3-quinuclidinone (3), as described in the Journal of Medicinal Chemistry, 18, 587 (1975) prepared as described in Warawa's method. When treated with L-tartaric acid, the preferred chiral organic acid, the (S)-isomer of 3 crystallized as its tartrate salt was obtained in 85-90% yield. Dynamic kinetic resolution was performed since the resolution gave only one isomer in 50% yield, with the remainder being the undesired enantiomer. Thus, the undesired (R)-isomer is converted to the (S)-isomer under the reaction conditions. The solvent used for the crystallization is an alcohol, preferably ethanol, in which the ketone 3 is soluble in the presence of an organic carboxylic acid, preferably acetic acid.

Compared to classical resolution methods taught in the literature, dynamic kinetic resolution provides minimization of losses, since the undesired enantiomer does not have to be discarded.

Optically active ketones can be recovered from this salt, and in a process in which the S-stereochemistry is maintained at C-2 and the S-cis-stereochemistry is predominantly controlled at the new carbon-nitrogen bond at C-3, Used in reductive alkylation with benzylamine.

Asymmetric reductive alkylation with benzylamine involves 1) by treating S-3 with benzylamine in the presence of an excess of a mild Lewis acid such as aluminum triisopropoxide or titanium tetraisopropoxide in an organic solvent, The imine is then reduced in situ with hydrogen over a noble metal catalyst to form the intermediate imine. Without limitation, a suitable solvent for the reaction is tetrahydrofuran and a preferred catalyst for the hydrogenation is Pt on carbon.

Process 2

Detailed description

The methods employed and the reagents employed in the preparation of the serial racems of amine 1 and its analogs will be obvious extensions to those skilled in the art. The present invention involves the dynamic resolution of ketone 3 by forming a salt with a chiral organic acid. As used herein, chiral organic acids are organic carboxylic acids with asymmetric centers and with stereoisomers, some of which are mirror images of each other (enantiomers). Chiral organic acids are also soluble in organic solvents.

An effective amount of a chiral organic acid is used. Preferably, the chiral organic acid is used in at least approximately equimolar amounts to the quinuclidone, although an excess of the chiral organic acid may be used; however, approximately equimolar amounts are preferably used. Tartaric acid is a preferred example. An organic solvent is used in which the racemic ketone is soluble but in which the resulting salt precipitates. Sufficient solvent is present to solubilize the quinuclidone and various reagents. The organic solvent is preferably alcohol, with ethanol being the preferred alcohol, and denatured alcohol being the preferred form of ethanol.

Addition of weak organic carboxylic acids aids in salt formation. The organic carboxylic acid may be a monocarboxylic acid or a polycarboxylic acid, however, preferably it is a monocarboxylic acid or a dicarboxylic acid. It is particularly preferred that it is a monocarboxylic acid. Carboxylic acids include, but are not limited to: acetic acid, propionic acid and butyric acid. A preferred acid is acetic acid.

As noted above, the organic carboxylic acid employed is present in an amount sufficient to affect salt formation and facilitate salt precipitation. Preferably, at least 1 equivalent of organic carboxylic acid is used relative to quinuclidone.

As used herein, the term "equivalent", when referring to an acid, means the amount in units of weight or mole, which contains 1 atomic weight or mole, respectively, of acidic hydrogen, i.e. the hydrogen which reacts with the base during neutralization. For example, if the acid is a monocarboxylic acid, such as acetic acid, then 1 mole of acetic acid produces 1 mole (equivalent) of acid. However, if the carboxylic acid is a dicarboxylic acid, such as oxalic acid, succinic acid, etc., then 1 mole of dicarboxylic acid produces 2 equivalents of acid.

Thus, if the organic acid is a monocarboxylic acid, it is preferred to use at least approximately equimolar amounts of the monocarboxylic acid relative to the quinuclidone, and if the carboxylic acid is a dicarboxylic acid, on a molar basis relative to the dicarboxylic acid , preferably using at least about 2 times the amount of quinuclidone. However, it is preferred to use an excess of organic carboxylic acid.

It is preferred that the quinuclidone, chiral organic acid and organic carboxylic acid are mixed together at near ambient temperature, but they may be mixed at temperatures as low as 0°C to the reflux temperature of the solvent. The reaction was allowed to proceed until precipitation of the (S)-salt isomer ceased, ie no precipitation was observed anymore.

Without wishing to be bound, it is believed that the combination of chiral organic acids with quinuclidones and organic carboxylic acids facilitates dynamic kinetic resolution. More particularly, under the reaction conditions, not only the precipitated S-isomer salt, but also the undesired R-isomer is converted into the S-isomer salt. Thus, since it is converted to the S isomer, little, if any, of the R isomer is discarded under the reaction conditions of the present invention.

In the second step of the present invention, chiral ketone S-3 is obtained from tartrate by neutralization of the S isomer, eg S-tartrate. The second step is preferably carried out in a biphasic mixture of organic solvent and water. Suitable organic solvents include, but are not limited to, toluene, ethyl acetate, and methyl t-butyl ether. A preferred organic solvent is toluene. Suitable bases for the neutralization reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. In a preferred embodiment, the salt is suspended in a biphasic solvent mixture and an aqueous base solution is added with cooling to maintain a temperature below 25°C until a pH of about 9 is reached. The optically active free base of S-3 was recovered as a solid from the organic layer.

Without limitation, an application is described here showing that antagonists of substance P can be prepared using chiral ketone S-3 without racemization. Other aldehydes, reducing agents for amines and deprotection methods can be envisioned by those skilled in the art from the literature on the racemic compounds. The third step in this scheme involves the formation of imines with nitrogen-containing organic amines, such as alkylamines, arylamines, or aralkylamines. Preferably, the alkyl group contains 1 to 6 carbon atoms, and the alkyl group may be straight or branched. Examples include methyl, ethyl, isopropyl, propyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl and hexyl. The term "aryl" when used alone or in combination is an aromatic compound containing 6, 10, 14 or 18 ring carbon atoms and a total of up to 25 carbon atoms. Examples include phenyl, naphthyl and the like. A preferred amine is benzylamine. The organic amine is reacted in situ in the presence of a mild Lewis acid to form the imine, which is then reduced to the corresponding amine by techniques known to those of ordinary skill in the art, such as by reduction over a noble metal catalyst and hydrogen. This method avoids possible racemization during the conversion of S-3 to S-4. Formation of the imine in the presence of a Bronsted acid leads to some racemization at C-2. No epimerization is seen if a Lewis acid is used to catalyze the imine formation followed by a direct reduction on the resulting mixture.

Suitable solvents for the imine formation reaction are any homogenate hydrocarbons such as dichloromethane, dichlorobenzene, chlorobenzene, dichloroethane, or other inert solvents such as ether solvents, including, but not limited to, THF , and hydrocarbons, including, but not limited to, toluene. Suitable Lewis acids include aluminum triisopropoxide and titanium tetraisopropoxide. A preferred Lewis acid is aluminum triisopropoxide. The Lewis acid is present in an amount effective to form an imine. The nitrogen-containing organic amine is preferably present in at least approximately equimolar amounts to ketone S-3, although excess amine may be present. In addition, it is preferred that a Lewis acid is present in at least a catalytically effective amount to aid in the conversion of ketone S-3 to the imine. Preferably, the Lewis acid is present in an at least equimolar amount to the ketone S-3, especially if the ketone S-3 is the limiting reagent. The resulting imine is reduced by standard techniques, such as by using a noble metal catalyst and hydrogen. Noble metal catalysts include platinum and palladium metals on various supports. A preferred catalyst is platinum on carbon. For example, a specific step of the method of the present invention is carried out by mixing S-3 and benzylamine in tetrahydrofuran as a solvent and aluminum triisopropoxide as a Lewis acid. The imine formation is preferably carried out at room temperature for 3 hours. A slurry of 5% Pt/C in THF was added, and the reaction was stirred for 15 hours at a hydrogen pressure of 75 psi under a hydrogen atmosphere. Separation of optically active S, S-4 from the reaction.

The above-described method of the present invention achieves significant advantages over conventional, classical resolution methods. The yield of the resolution step, ie the first contacting step, is greater than 50%, which is the maximum possible with typical resolution. The undesired isomer is converted to the desired isomer, which is separated from the mixture under the reaction conditions. This results in increased productivity and cost savings. The use of quinuclidone as the single enantiomer allows the asymmetric synthesis of antagonists of substance P in optically pure form by a number of routes, and reduces the problems associated with resolution at a later stage. The problems associated with racemization during reductive amination are eliminated by using Lewis acid-catalyzed imine formation and in situ catalytic hydrogenation.

The method described here can be used to prepare S,S-cis-2-benzhydryl-3-benzyl-aminoquinuclidone from a mixture of the R and S isomers of quinuclidone. The R isomer may be present in larger amounts or vice versa . The above procedure can also be used to form the title compound from racemic 2-benzohydroyl-3-quinuclidinone, which is a common starting material.

The products formed by the methods described above are substantially enantiomerically pure, ie substantially free of any other stereoisomers, ie RR, RS or SR products. Preferably, it contains less than 10% impurities from other stereoisomers, and more preferably less than about 5% impurities from other stereoisomers, and even more preferably less than about 1% other stereoisomers.

The product so formed is also preferably substantially pure, ie contains less than 10% impurities, and more preferably contains less than 5% impurities. However, if desired, the (S,S)-cis- 2-Benzhydryl-3-benzylaminoquinuclidine.

The following examples are intended as illustrations of some preferred embodiments of the invention and are not meant to limit the invention.

Example 1

(2S)-Benzhydryl-3-quinuclidone L-tartrate

Dissolve racemic 2-benzhydryl-3-quinuclidinone (52.45g, 180mmol) in denatured alcohol (525ml) containing acetic acid (10.4ml, 180mmol) and add L-tartaric acid (27g, 180mmol ). The mixture was heated to reflux for 12 hours, then allowed to cool to room temperature for 1 hour. The solid was collected and dried under vacuum at 40°C for 12 hours. The yield of the desired salt was 69.9 g, which is 88% of theory.

Example 2

(2S)-Benzhydryl-3-quinuclidone (S-3)

L-tartrate (69.9 g, 158 mmol) from the previous example was suspended in toluene (700 ml), cooled with an ice-water bath, while a saturated solution of sodium bicarbonate (500 ml) was added dropwise maintaining a maximum temperature of 25 °C . The clear biphasic mixture was stirred at 25°C for 20 minutes, and the layers were separated. The organic layer was washed with water (100ml), the layers were separated and the organics were dried over sodium sulfate. The organics were filtered, and evaporated in vacuo to provide the desired optically active ketone as a colorless solid, 45.66 g, 99% yield. Mp145-146°C. ¹ HMR (300MHz, CDCl ₃ ) δ1.86-2.00(m, 4), 2.41-2.43(m, 1), 2.54-2.59(m, 2), 3.08(t, 2), 3.98(d, 1) , 4.55(d, 1), 7.17(m, 8), 7.38-7.41(m, 2).

Example 3

(S, S)-2-Benzhydryl-3-benzylaminoquinuclidine (S, S-4)

The case of using aluminum triisopropoxide:

(2S)-Benzhydryl-3-quinuclidinone (0.50 g, 1.0 equiv, 1.72 mmol) was dissolved in anhydrous THF (2 ml) under nitrogen. Then, benzylamine (0.21 ml, 1.1 equiv, 1.89 mmol) was added followed by a solution of aluminum isopropoxide (0.42 g, 1.2 equiv, 2.06 mmol) in 2 ml of anhydrous THF. The solution was stirred for 3 hours. To this colorless solution was then added a slurry of 5% Pt/C (0.063 g, Degussa F101RA/W, ~60% wet) in 1 ml anhydrous THF. The reaction was placed in a Parr reactor pressurized to 75 psi _H2 and allowed to react at room temperature for 15 hours. The reaction mixture was poured into 15 ml of 2M hydrochloric acid, then filtered, basified with 1M sodium hydroxide, and extracted with 50 ml of methyl tert-butyl ether (MTBE). The MTBE layer was dried over magnesium sulfate followed by removal of solvent in vacuo to give a white crystalline solid. It was analyzed as all cis isomers (<2% trans isomers), >99% ee (no other isomers observed).

The case of using titanium tetraisopropoxide:

(2S)-Benzhydryl-3-quinuclidone (9.00 g, 30.9 mmol) was dissolved in 75 ml dry THF. The solution was transferred through the port into a 300 ml autoclave with a fixed hydrogenation head while maintaining a positive flow of nitrogen. Benzylamine (3.7ml, 33.9mmol) was added followed by titanium(IV) isopropoxide (10.9ml, 36.9mmol) via the same port on the hydrogenator head with stirring at 300rpm. Seal the ports and pressure test the autoclave (150 psi nitrogen) while stirring the reaction mixture at 300 rpm. After 3.0 hours at 25°C, the pressure was released and a slurry of 5% Pt/C (1.13 g; 59.4% wet) in 3 ml THF was added through the port via a syringe (14-gauge needle) under a positive flow of nitrogen. The rest of the catalyst was slurried with additional THF (2ml) and added to the reaction. The ports were sealed and the autoclave was pressurized to 75 psi with hydrogen, then slowly vented. Repeat this step three times. The final hydrogen pressure was adjusted to 75 psi and the reaction mixture was hydrogenated overnight (12 hours) with stirring maintained at 600 rpm. The vessel was then vented, then pressurized with nitrogen (100 psi) and vented. The reactor was pressurized and vented three more times with nitrogen.

Under a positive flow of nitrogen, 42 ml of ice-cold 12.4% hydrochloric acid (28 ml of water + 14 ml of 37% HCl) was added slowly, the reaction mixture was stirred under nitrogen at 25 °C and 900 rpm for 1 hour, then pressure transferred to a 250 ml Erlenmeyer flask. Toluene (50ml) and 30ml of 10% hydrochloric acid were introduced into the hydrogenator. The reaction mixture was stirred at 900 rpm for 30 minutes before pressure transfer to the Erlenmeyer flask. The combined biphasic heterogeneous solution was vacuum filtered through a 1 cm pad of diatomaceous earth to remove the Pt/C catalyst. The filter cake was further washed with aqueous 10% hydrochloric acid (100ml). The clear filtrate phases were separated immediately and the organic layer was removed and discarded. With stirring and cooling, 50 ml of toluene was added and the pH was adjusted to about 13 by slow addition of 50% sodium hydroxide (30 ml). The biphasic slurry was filtered through a 1 cm pad of diatomaceous earth to remove titanium salts. The filter cake was washed with toluene (2 x 50ml), then the layers were separated and the toluene layer was concentrated at 80°C until the toluene volume was reduced to 20ml. Then, 40 ml of n-heptane were added and the mixture was slowly cooled to 10°C over 2-3 hours (0.5 g of seeds (-5%) were added at 55°C). The precipitate was filtered, washed with 40 ml of toluene/n-heptane 1/6 (v/v), and dried under vacuum at 40°C. Yield of colorless solid 7.3 g, 61% of theory.

Claims (34)

1. the method for preparing (S, S)-cis-2-benzhydryl-3-benzylaminoquinucidine, the method may further comprise the steps: In the presence of an organic solvent and an effective amount of an organic carboxylic acid, a compound containing a mixture of R- and S-isomers and having the formula:

converting said R-isomer into an acid salt of said S-isomer by contacting with an effective amount of a chiral organic acid, said organic solvent capable of solubilizing said R- and S-isomer-containing a mixture of said compounds while precipitating said acid salt, and said organic carboxylic acid is different from said chiral organic acid; Neutralization of the acid salt with a base provides the S-isomer of the chiral ketone of the formula; and Reaction of the chiral ketone with an organic amine in the presence of a Lewis acid provides the corresponding imine and reduces the imine. 2. The method of claim 1, wherein said compound is present as a racemic mixture. 3. The method of claim 1, wherein the acid salt is the tartrate salt of (2S)-benzhydryl-3-quinuclidinone. 4. The method of claim 1, wherein the chiral organic acid is L-tartaric acid. 5. The method of claim 1, wherein said effective amount of said chiral organic acid used is at least 1 equivalent or more. 6. The method of claim 1, wherein the organic solvent is an alcohol. 7. The method of claim 5, wherein the alcohol is ethanol. 8. The method of claim 6, wherein the alcohol is denatured alcohol. 9. The method of claim 1, wherein the organic carboxylic acid is acetic acid, propionic acid, or butyric acid. 10. The method of claim 9, wherein the organic carboxylic acid is acetic acid. 11. The method of claim 1, wherein said effective amount of said organic carboxylic acid used is at least 1 equivalent relative to said compound. 12. The method of claim 1, wherein the base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. 13. The method of claim 1, wherein the base is added under cooling to maintain a temperature below 25°C until a pH of about 9 is reached. 14. The method of claim 1, wherein said neutralization is performed in the presence of a biphasic solvent mixture. 15. The method of claim 14, wherein the biphasic solvent mixture comprises a second organic solvent and water. 16. The method of claim 15, wherein the second organic solvent is toluene, ethyl acetate or methyl t-butyl ether. 17. The method of claim 1, wherein the Lewis acid is an aluminum salt. 18. The method of claim 16, wherein the aluminum salt is aluminum triisopropoxide. 19. The method of claim 1, wherein the Lewis acid is a titanium salt. 20. The method of claim 19, wherein the titanium salt is titanium tetraisopropoxide. 21. The method of claim 1, wherein at least 1 equivalent or more of said Lewis acid is used relative to the S isomer of said chiral ketone. 22. The method of claim 1, wherein the imine is reduced by reacting the imine with a reducing agent in the presence of a noble metal catalyst. 23. The method of claim 22, wherein the noble metal catalyst is a supported palladium or supported platinum catalyst. 24. The method of claim 22, wherein the noble metal catalyst is palladium on carbon. 25. The method of claim 22, wherein the reducing agent is hydrogen gas. 26. The method of claim 1, wherein the organic amine is an aralkylamine. 27. The method of claim 26, wherein the aralkylamine is benzylamine. 28. The method of claim 1, wherein the acid salt is produced at a yield of greater than 50%. 29. The method of claim 28, wherein the yield is 85%-90%. 30. The method of claim 1, wherein the imine is reduced just after it is formed. 31. 2 (S)-Benzhydryl-3-quinuclidinone as a salt which is substantially enantiomerically pure. 32. The salt of claim 30 which is tartrate. 33. A substantially enantiomerically pure 2(S)-benzhydryl-3-quinuclidinone. 34. A substantially enantiomerically pure imine of 2(S)-benzhydryl-3-quinuclidinone.